High yielding alkylations of unactivated sp3 and sp2 centres with alkyl-9-BBN reagents using an NHC-based catalyst: Pd-PEPPSI-IPr

Article abstract of DOI:10.1039/b715081d

High yielding, room temperature cross couplings of unactivated alkyl bromides and aryl bromides/chlorides with alkyl-9-BBN reagents has been achieved using an NHC-based catalyst (Pd-PEPPSI-IPr) via a general, functional-group tolerant and easily implemented protocol. The Royal Society of Chemistry.

Full text of DOI:10.1039/b715081d

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COMMUNICATION
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High yielding alkylations of unactivated sp3 and sp2 centres with alkyl-
9-BBN reagents using an NHC-based catalyst: Pd-PEPPSI-IPr{
Cory Valente, Sylvia Baglione, David Candito, Christopher J. O’Brien and Michael G. Organ*
Received (in Cambridge, UK) 1st October 2007, Accepted 23rd November 2007
First published as an Advance Article on the web 7th December 2007
DOI: 10.1039/b715081d
successful use in the Negishi,10 Kumada-Tamao-Corriu,11 and
sp2–sp2 Suzuki–Miyaura reactions.12 Herein, we further expand
High yielding, room temperature cross couplings of unactivated
alkyl bromides and aryl bromides/chlorides with alkyl-9-BBN
the scope of Pd-PEPPSI-IPr by reporting on its success in
achieving high yielding, room temperature alkylations of unac-
tivated alkyl and aryl bromides and aryl chlorides with alkyl-9-
BBN reagents.
reagents has been achieved using an NHC-based catalyst (Pd-
PEPPSI-IPr) via a general, functional-group tolerant and easily
implemented protocol.
Since its introduction in 1968 by Brown,1 9-borabicyclo[3.3.1]no-
nane (9-BBN) has been used widely as a chemo- and regioselective
hydroborating reagent for alkenes and alkynes.2 The resultant
alkyl- and alkenyl-9-BBN species, respectively, are easily accessible
and synthetically useful intermediates exploited in a variety of
ways, including as effective transmetalating agents in Pd- and Ni-
mediated cross coupling reactions.3 This last feature made way for
the first reported alkyl–alkyl coupling reaction when in 1992
Suzuki and co-workers successfully coupled unactivated sp3-
iodides with alkyl-9-BBN reagents in the presence of Pd(PPh3)4.4
These results implied that not only were unactivated alkyl halides
accessible coupling substrates but that the oxidative addition
adduct (i.e. alkyl-PdII-I) was sufficiently stable to undergo
intermolecular transmetalation rather than intramolecular
b-hydride elimination (Fig. 1). Despite this finding, follow-up
investigations remained scarce until 2001 when Fu and co-workers
disclosed a Pd(OAc)2/PCy3 catalyst system capable of coupling
alkyl-9-BBN reagents with unactivated alkyl bromides.5 Since
then, the majority of studies achieving sp3–sp3 Suzuki–Miyaura
couplings have done so by employing exchangeable trialkylpho-
sphines that are sufficiently electron rich to ‘activate’ Pd toward
oxidative addition, while possessing suitable steric bulk to enhance
reductive elimination and disfavor agostic Pd–H interactions and
ensuing b-hydride elimination.6
An optimization study for the coupling of n-heptyl-9-BBN with
1-bromo-3-phenylpropane was carried out (Table 1). Whereas
anhydrous bases CsF, K2CO3 and K3PO4 were ineffective,
K3PO4?H2O provided excellent conversion to 1-phenyldecane
(entries 1–4). Fu and co-workers have submitted that
K3PO4?H2O generates a hydroxyl-bound ‘‘borate’’ complex
in situ, which is believed to be the active transmetalating agent.5
This is inline with mechanistic studies carried out by Soderquist
and Matos,13 and consistent with the finding that KOH(s) furnishes
the same yield (entry 5). Comparable results were obtained when
using 4 or 2 mol% of 1 while decreasing to 1 mol% resulted in a
slight erosion in yield (entries 4, 6 and 7). Omission of 1 provided
no product (entry 8). In all studies conducted, no b-hydride
elimination product was observed.
N-Heterocyclic carbenes (NHCs) are proving to be very
productive in a range of applications for a variety of reasons.7
The NHC is an excellent s-doner, their Pd-complexes are very
insensitive to air and moisture and they have a negligible
dissociation constant from the metal. In 2004, Caddick and
Cloke reported the first and to-date only known alkyl–alkyl
Suzuki–Miyaura coupling utilizing an NHC-based catalyst
generated in situ from imidizaolium salt IPr?HCl and Pd2(dba)3.8
Their attempt required slightly elevated temperatures (40 uC)
to couple primary alkyl bromides in yields ranging from
28–56%.
In 2006, our group disclosed the highly active, air and moisture
stable complex Pd-PEPPSI-IPr (1).9 We have since relayed its
Department of Chemistry, York University, 4700 Keele Street, Toronto,
Ontario, M3J 1P3, Canada. E-mail: organ@yorku.ca
{ Electronic supplementary information (ESI) available: Experimental
procedures and compound data. See DOI: 10.1039/b715081d
Fig. 1 Pd-PEPPSI-IPr (1), its proposed activation and catalytic cycle in
couplings involving alkyl boranes.
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Table 1 Optimization study for Suzuki–Miyaura couplings with sp3
centres
Upon expanding the protocol to more elaborate substrates
(Table 2), it became apparent that only moderate yields of product
were accessible using a 2 mol% catalyst loading and/or less than
1.6 equivalents of the alkylborane reagent (2, 3 and 4). In these
experiments, the remaining mass balance was predominately
unaltered alkyl bromide. Increasing the catalyst loading to
4 mol% and borane equivalents to 1.6 (based on the electrophile)
generally provided optimal results. It was also discovered that
diluting the reaction mixture had a detrimental effect on the yield,
as can be seen with the preparation of 4. It is not clear at which
step in the catalytic cycle concentration is important because
starting materials accounted for the remainder of the mass balance
and no byproducts, such as b-hydride elimination, were observed.
In any case, limiting the amount of solvent required and waste
generated are two attractive features when considering large-scale
amenability.
Entry Borane equiv.a Base (equiv.)a
1 mol%a Conversion (%)b
1
2
3
4
5
6
7
8
9c
a
1.6
1.6
1.6
1.6
1.6
1.3
1.3
1.3
1.3
CsF (1.6)
K3PO4 (1.6)
K2CO3 (1.6)
K3PO4?H2O (1.6) 4
KOH(s) (1.6)
K3PO4?H2O (1.3) 2
K3PO4?H2O (1.3) 1
K3PO4?H2O (1.3) 0
K3PO4?H2O (2.6) 4
4
4
4
8
29
0
85
85
87
76
0
4
77
b
Equivalents based on 3-bromo-1-phenylpropane.
Percent
conversion was assessed by GC analysis using undecane as a
calibrated internal standard; reactions were performed in duplicate.
THF used as solvent.
c
With these results in hand, the substrate scope was further
expanded to include amides (3 and 5), nitriles (8 and 9), esters (6–8)
and silyl ethers (4), providing 62–92% yields of isolated
Table 2 Substrate study for Suzuki–Miyaura coupling with alkyl
bromidesa
Table 3 Substrate study for Suzuki–Miyaura coupling with aryl
chlorides and bromidesa
a
All reactions were performed in duplicate and the average yield
reported. Final concentration ~ 0.8 M based on alkyl bromide.
b
Reaction performed with 1.3 equiv. of alkyl-9-BBN and 4 mol% 1.
Reaction performed with 1.3 equiv. of alkyl-9-BBN and 2 mol% 1.
Reaction concentration ~ 0.6 M based on alkyl bromide.
c
a
All reactions were performed in duplicate and the average yield
reported. Final concentration ~ 0.8 M based on alkyl halide.
d
736 | Chem. Commun., 2008, 735–737
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product in less than 16 h at room temperature. Selectivity in
9-BBN hydroborations provided access to disubstituted olefins
3 and 6. The protocol is easily implemented, requires only
standard laboratory techniques, and avoids the use of an aqueous
work-up.
Notes and references
1 E. F. Knights and H. C. Brown, J. Am. Chem. Soc., 1968, 90, 5280–5281.
2 M. Zaidlewicz, in Comprehensive Organometallic Chemistry, ed.
G. Wilkinson, F. G. A. Stone and E. W. Abel, Pergamon,Oxford,
1982, 7, pp 199–254.
3 S. R. Chemler, D. Trauner and S. J. Danishefsky, Angew. Chem., Int.
Ed., 2001, 40, 4544–4568.
4 T. Ishiyama, S. Abe and A. Suzuki, Chem. Lett., 1992, 691–694.
5 M. R. Netherton, C. Dai, K. Neuschutz and G. C. Fu, J. Am. Chem.
Soc., 2001, 123, 10099–10100.
6 For a review, see: A. C. Frisch and M. Beller, Angew. Chem., Int. Ed.,
2005, 44, 674–688.
7 (a) E. A. B. Kantchev, C. J. O’Brien and M. G. Organ, Angew. Chem.,
Int. Ed., 2007, 46, 2768–2813; (b) E. A. B. Kantchev, C. J. O’Brien and
M. G. Organ, ChemFiles, 2006, 6, 1–9; Catalysis: PEPPSITM Catalyst; (c)
N-Heterocyclic carbenes in synthesis; S. P. Nolan Ed.; Wiley-VCH:
Weinheim, 2006; (d) W. A. Herrmann, Angew. Chem., Int. Ed., 2002, 41,
1290–1309.
Alkylation of aryl bromides and chlorides were also achieved
without modification of the reaction conditions (Table 3). Phenols
(10), esters (11, 13, 14 and 17), anilines (15), carbamates (11) and
aldehydes (17) were all coupled directly in good yield, circumvent-
ing any need to implement protecting group chemistry.
Additionally, substituted furans (12 and 18), thiophenes (12,
14 and 16), indoles (11) and pyridine derivatives (13 and 18)
were found to be compatible heterocycles with these reaction
conditions.
In conclusion,
a general, easily implemented and high
8 K. Arentsen, S. Caddick, F. G. N. Cloke, A. P. Herring and
P. B. Hitchcock, Tetrahedron Lett., 2004, 45, 3511–3515.
9 (1,3-Diisopropylimidazol-2-ylidene)(3-chloropyridyl)palladium(II)
dichloride. PEPPSI is an acronym for P_yridine E_nhanced P_recatalyst
P_reparation S_tabilization and _Initiation.
10 M. G. Organ, S. Avola, I. Dubovyk, N. Hadei, E. A. B. Kantchev,
C. J. O’Brien and C. Valente, Chem.–Eur. J., 2006, 12, 4749–4755.
11 M. G. Organ, M. Abdel-Hadi, S. Avola, N. Hadei, J. Nasielski,
C. J. O’Brien and C. Valente, Chem.–Eur. J., 2007, 12, 150–157.
12 C. J. O’Brien, E. A. B. Kantchev, C. Valente, N. Hadei, G. A. Chass,
A. Lough, A. C. Hopkinson and M. G. Organ, Chem.–Eur. J., 2006, 12,
4743–4748.
yielding protocol for the coupling of unactivated alkyl
bromides and aryl bromides and chlorides with alkyl-9-BBN
reagents has been established. The vast number of reports on
the Suzuki–Miyaura reaction, and cross couplings in general,
speaks to the difficulty associated with finding any single,
generally-applicable catalyst. Although this goal may well be
intrinsically unattainable, Pd-PEPPSI-IPr is being established as a
broadly applicable catalyst, realizing a range of cross couplings,
herein expanded to include alkylations via the Suzuki–Miyaura
reaction.
13 K. Matos and J. A. Soderquist, J. Org. Chem., 1998, 63, 461–470.
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